Donepezil hydrochloride, which is chemically known as 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl)methyl piperidine hydrochloride [formula I]
is used in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. It is available for oral administration in film-coated tablets containing 5 or 10 mg of donepezil hydrochloride.
Donepezil hydrochloride is well known in the art and was first disclosed in U.S. Pat. No. 4,895,841, hereinafter referred to as the '841 patent. As described therein, donepezil hydrochloride is prepared by reacting 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of a strong base such as lithium diisopropyl amide followed by a reduction step (Examples 3 and 4) with a palladium carbon catalyst in tetrahydrofuran (THF). The residue was purified by making use of silica gel column chromatography. This process, however, suffers from certain evident limitations. The procedure laid down for reduction of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methyl piperidine is not industrially feasible. It entails the use of column chromatography for the purification of the hydrogenated residue, which cannot be carried out industrially. Further, the process makes use of THF, which is a highly flammable solvent and may form explosive peroxide vapors. Moreover, the overall yield of donepezil HCl is reported to be 50.8%. The purity of the product obtained is not disclosed in the patent.
U.S. Pat. No. 5,606,064, hereinafter referred to as the '064 patent, and U.S. Pat. No. 6,252,081 describe a process for the preparation of donepezil wherein 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methyl pyridinium salt is reduced to yield donepezil. The reduction of the olefinic bond and a pyridinium ring in the presence of a benzyl group is difficult to achieve under the conditions disclosed in the patent. Further, the reaction requires at least 24 hours to complete (Example 6).

The major disadvantage of the process is that the reaction is carried out in the presence of methanol and platinum dioxide. The use of an expensive catalyst is not viable industrially. Moreover, on repeating the above process, unwanted side products are produced, such as a partly hydrogenated impurity of formula III
which is formed to an extent of 5%. This impurity is difficult to separate in the final crystallization, hence requires purification by column chromatography/repeated purification resulting in poor yield, hence making the process not feasible on an industrial scale. These impurities also affect the overall yield of the final product. Further, the purity of the product obtained is not disclosed in the patent.
U.S. Pat. No. 6,649,765 and US Patent Application published under no. 2004/0158070A1 describe the reduction of 5,6-dimethoxy-2-(pyridin-4-yl)methylene-indan-1-one using a noble metal oxide catalyst (platinum oxide) in a mixture of solvents such as acetic acid and methanol at 10-45 psi gauge pressure followed by benzylation to obtain donepezil hydrochloride. Besides making the process expensive, it is not industrially viable. Further, the purity of the product obtained is not disclosed in these patents.

PCT Publication No. WO2004/082685 describes the preparation of donepezil which comprises a two-step reduction starting from 5,6-dimethoxy-2-(pyridine-4-yl)methylene-indan-1-one via the preparation of intermediate 5,6-dimethoxy-2-(4-pyridyl)methyl-indan-1-one using methanol as one of the solvents followed by benzylation.

The above process is also time consuming and difficult to carry out as it involves multiple steps.
US Patent Application published under the No. 2007/0135644A1 discloses the preparation of donepezil hydrochloride by reducing 5,6-dimethoxy-2-[1-(4-pyridinyl)methylidene]-1-indanone tosylate with 10% Pd/C catalyst in demi-water at 70-95° C., at 10 bar for 8 hours. The mixture is extracted three times with 1-butanol to afford a residue which is purified with methyl-tert-butyl ether to obtain 5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone, followed by condensation with benzyl chloride in toluene for 8 hours at 145° C. to yield donepezil which is further converted to donepezil hydrochloride.

This process involves reduction at a high pressure of 10 bar and temperature of 70-95° C. which leads to impurities. Further, the benzylation reaction requires a high temperature of 145° C. for 8 hours. The work-up process is very lengthy thereby making the whole process industrially unfavorable.
PCT Publication No. WO 2008/010235 discloses a method for preparation of donepezil hydrochloride wherein 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methyl piperidine, is reduced with metal borohydride in the presence of a catalytic amount of a cobalt salt in a large volume of THF as solvent to yield donepezil hydrochloride. This process is not viable industrially due to use of costly cobalt catalyst.
The prior art procedures for the preparation of donepezil have certain disadvantages, such as multiple reduction steps, and/or chromatographic separation of intermediates, side-product formation, giving low yields. These properties hinder the large-scale production of donepezil hydrochloride.
Therefore, there is a need to develop an industrially feasible, cost effective and environmentally friendly process for the preparation of donepezil hydrochloride of formula (I) with high purity.